Table 1.

Potential indirect approaches for inhibition of CBS activity. Please note that most of these approaches are only theoretical and all of them are expected to induce broad-based cellular side effects well beyond the regulation of CBS.

Principal Approach	Effect on CBS	Pharmacological Modulators	Potential Off-Target Effects
Inhibition of SAM binding to CBS	Partial inhibition of CBS catalytic activity. Destabilization of the CBS tetramer	MAT inhibitors, competitors of SAM binding to CBS (SAM analogs)	Inhibition of other SAM-dependent enzymes and processes
Stimulation of CO or NO binding to CBS	Partial inhibition of CBS catalytic activity	NO or CO donors	Activation other NO- or CO-dependent enzymes and processes (e.g., vasodilatation, hypotension)
Inhibition of CBS phosphorylation	Partial inhibition of CBS catalytic activity	Kinase inhibitors	Inhibition of other enzymes phosphorylated by the same kinase; modulation of multiple downstream processes
Inhibition of CBS S-glutathionylation	Partial inhibition of CBS catalytic activity	Glutathione S-transferase inhibitors	Inhibition of other enzymes glutathionylated by the same S-transferase
Stimulation of SUMOylation	Proteolytic degradation of CBS; reduced total cellular CBS activity	Possible approach may be the modulation of upstream processes, e.g., E1 activating enzyme (the heterodimer SAE1/2) or E2 conjugase (Ubc9). No known pharmacological agents	Broad dysregulation of protein processing and protein degradation
Stimulation of ubiquitination	Proteasomal degradation of CBS; reduced total cellular CBS activity	Pharmacological activation of E1 activating, E2 conjugating and E3 ligating enzymes (only theoretical; no known inhibitors). Or: pharmacological inhibition of deubiquitinases (this approach has been proposed to degrade undruggable targets for cancer therapy)	Broad dysregulation of protein processing and protein degradation
Inhibition of CBS proteolytic cleavage	Inhibition of the proteolytic conversion of CBS into the highly active 45-kDa form; inhibition of cellular CBS activity	Proteolysis inhibitors (not suitable as a practical approach; selective intracellular delivery of protease inhibitors is not feasible)	Broad dysregulation of protein processing and protein degradation
Activation of Lon protease	Proteolytic degradation of CBS into inactive forms	Lon activators (e.g., Heat Shock Protein Q) exist but only as experimental tools	Broad dysregulation of mitochondrial protein homoeostasis
Inhibiting substrate availability by blocking cystine transport into the cell	Lower CBS activity	Cystine/glutamate antiporter system blockers	Broad dysregulation of sulfur-containing amino acid homeostasis